This project will test genetic risk markers for smoking trajectory from adolescence through young adulthood in a cohort collected during the initial program project. We will concentrate on genetic risk markers in neuronal nicotinic acetylcholine receptors (nAChRs) but also will consider a limited number of other candidate genes for which there is strong empirical support. We reported previously that CHRNA5-A3-B4 haplotype association with adult nicotine dependence in Whites was more robust in smokers who began daily smoking prior to age 17. This strongly suggests a heightened sensitivity to these risk markers in adolescents. This project uses a unique, prospectively studied adolescent cohort with a rich set of longitudinal phenotypes characterizing smoking progression. We will test possible additive and Interactive effects of genetic risk markers and other variables known to be associated with smoking trajectory (e.g., gender, race, substance use, depression, peer influence and parental smoking). Also, we will examine hypotheses regarding the mediation of genetic associations with smoking trajectoiy by short-term affect regulation and alleviation of nicotine withdrawal by cigarette smoking. Further, we will determine the genetic architecture of nAChR genes within the racial/ethnic groups represented in the study cohort so haplotype-specific genetic risk markers can be tested across races.